Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis.
Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis.
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DOI：
10.1186/1471-2121-14-32
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发表时间：
2013-07-09
期刊：
影响因子：
--
通讯作者：
Boise LH
中科院分区：
文献类型：
--
作者：
Brentnall M;Rodriguez-Menocal L;De Guevara RL;Cepero E;Boise LH
细胞凋亡是一种由Bcl-2家族和caspase家族蛋白调节的程序性细胞死亡形式。细胞色素c释放后负责执行细胞死亡的半胱天冬酶级联反应得到了很好的描述;然而，半胱天冬酶-9、半胱天冬酶-3和半胱天冬酶-7在该过程中的不同作用尚未完全确定。在这里，我们展示了这些半胱天冬酶在细胞死亡过程中的几个独特的功能。特异性抑制胱天蛋白酶-9允许细胞色素c的有效释放，但阻断线粒体形态和ROS产生的变化。我们表明，半胱天冬酶-9可以裂解成tBid在氨基酸59和投标的这种裂解是必需的ROS生产后血清撤出。我们还证明，caspase-3缺陷的MEFs是不太敏感的内在细胞死亡刺激，但有较高的活性氧产生。相比之下，半胱天冬酶-7缺陷型MEFs不抵抗内在细胞死亡，但仍附着于ECM。综上所述，这些数据表明，caspase-9是线粒体形态学变化和ROS生产所需的裂解和激活投标成tBid。在被半胱天冬酶-9激活后，半胱天冬酶-3抑制ROS产生并且是有效执行凋亡所需的，而效应物半胱天冬酶-7是凋亡细胞脱离所需的。
Apoptosis is a form of programmed cell death that is regulated by the Bcl-2 family and caspase family of proteins. The caspase cascade responsible for executing cell death following cytochrome c release is well described; however the distinct roles of caspases-9, -3 and -7 during this process are not completely defined. Here we demonstrate several unique functions for each of these caspases during cell death. Specific inhibition of caspase-9 allows for efficient release of cytochrome c, but blocks changes in mitochondrial morphology and ROS production. We show that caspase-9 can cleave Bid into tBid at amino acid 59 and that this cleavage of Bid is required for ROS production following serum withdrawal. We also demonstrate that caspase-3-deficient MEFs are less sensitive to intrinsic cell death stimulation, yet have higher ROS production. In contrast, caspase-7-deficient MEFs are not resistance to intrinsic cell death, but remain attached to the ECM. Taken together, these data suggest that caspase-9 is required for mitochondrial morphological changes and ROS production by cleaving and activating Bid into tBid. After activation by caspase-9, caspase-3 inhibits ROS production and is required for efficient execution of apoptosis, while effector caspase-7 is required for apoptotic cell detachment.
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